1ssp: Difference between revisions
New page: left|200px<br /> <applet load="1ssp" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ssp, resolution 1.9Å" /> '''WILD-TYPE URACIL-DNA... |
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[[Image:1ssp.gif|left|200px]]<br /> | [[Image:1ssp.gif|left|200px]]<br /><applet load="1ssp" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1ssp, resolution 1.9Å" /> | caption="1ssp, resolution 1.9Å" /> | ||
'''WILD-TYPE URACIL-DNA GLYCOSYLASE BOUND TO URACIL-CONTAINING DNA'''<br /> | '''WILD-TYPE URACIL-DNA GLYCOSYLASE BOUND TO URACIL-CONTAINING DNA'''<br /> | ||
==Overview== | ==Overview== | ||
Three high-resolution crystal structures of DNA complexes with wild-type | Three high-resolution crystal structures of DNA complexes with wild-type and mutant human uracil-DNA glycosylase (UDG), coupled kinetic characterizations and comparisons with the refined unbound UDG structure help resolve fundamental issues in the initiation of DNA base excision repair (BER): damage detection, nucleotide flipping versus extrahelical nucleotide capture, avoidance of apurinic/apyrimidinic (AP) site toxicity and coupling of damage-specific and damage-general BER steps. Structural and kinetic results suggest that UDG binds, kinks and compresses the DNA backbone with a 'Ser-Pro pinch' and scans the minor groove for damage. Concerted shifts in UDG simultaneously form the catalytically competent active site and induce further compression and kinking of the double-stranded DNA backbone only at uracil and AP sites, where these nucleotides can flip at the phosphate-sugar junction into a complementary specificity pocket. Unexpectedly, UDG binds to AP sites more tightly and more rapidly than to uracil-containing DNA, and thus may protect cells sterically from AP site toxicity. Furthermore, AP-endonuclease, which catalyzes the first damage-general step of BER, enhances UDG activity, most likely by inducing UDG release via shared minor groove contacts and flipped AP site binding. Thus, AP site binding may couple damage-specific and damage-general steps of BER without requiring direct protein-protein interactions. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1SSP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with URA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Uridine_nucleosidase Uridine nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.3 3.2.2.3] Full crystallographic information is available from [http:// | 1SSP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=URA:'>URA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Uridine_nucleosidase Uridine nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.3 3.2.2.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SSP OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Uridine nucleosidase]] | [[Category: Uridine nucleosidase]] | ||
[[Category: Bharati, S.]] | [[Category: Bharati, S.]] | ||
[[Category: Krokan, H | [[Category: Krokan, H E.]] | ||
[[Category: Mol, C | [[Category: Mol, C D.]] | ||
[[Category: Parikh, S | [[Category: Parikh, S S.]] | ||
[[Category: Slupphaug, G.]] | [[Category: Slupphaug, G.]] | ||
[[Category: Tainer, J | [[Category: Tainer, J A.]] | ||
[[Category: URA]] | [[Category: URA]] | ||
[[Category: dna]] | [[Category: dna]] | ||
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[[Category: uracil]] | [[Category: uracil]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:04:48 2008'' | ||
Revision as of 16:04, 21 February 2008
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WILD-TYPE URACIL-DNA GLYCOSYLASE BOUND TO URACIL-CONTAINING DNA
OverviewOverview
Three high-resolution crystal structures of DNA complexes with wild-type and mutant human uracil-DNA glycosylase (UDG), coupled kinetic characterizations and comparisons with the refined unbound UDG structure help resolve fundamental issues in the initiation of DNA base excision repair (BER): damage detection, nucleotide flipping versus extrahelical nucleotide capture, avoidance of apurinic/apyrimidinic (AP) site toxicity and coupling of damage-specific and damage-general BER steps. Structural and kinetic results suggest that UDG binds, kinks and compresses the DNA backbone with a 'Ser-Pro pinch' and scans the minor groove for damage. Concerted shifts in UDG simultaneously form the catalytically competent active site and induce further compression and kinking of the double-stranded DNA backbone only at uracil and AP sites, where these nucleotides can flip at the phosphate-sugar junction into a complementary specificity pocket. Unexpectedly, UDG binds to AP sites more tightly and more rapidly than to uracil-containing DNA, and thus may protect cells sterically from AP site toxicity. Furthermore, AP-endonuclease, which catalyzes the first damage-general step of BER, enhances UDG activity, most likely by inducing UDG release via shared minor groove contacts and flipped AP site binding. Thus, AP site binding may couple damage-specific and damage-general steps of BER without requiring direct protein-protein interactions.
DiseaseDisease
Known diseases associated with this structure: Immunodeficiency with hyper IgM, type 4 OMIM:[191525]
About this StructureAbout this Structure
1SSP is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Uridine nucleosidase, with EC number 3.2.2.3 Full crystallographic information is available from OCA.
ReferenceReference
Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil-DNA glycosylase with DNA., Parikh SS, Mol CD, Slupphaug G, Bharati S, Krokan HE, Tainer JA, EMBO J. 1998 Sep 1;17(17):5214-26. PMID:9724657
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